We study the two major subtypes of unipolar depression, melancholia and atypical depression and focus on four interrelated areas: elucidation of their pathophysiology; identification of biological markers to aid positional cloning; understanding the mechanism of action of antidepressant agents, and identification of the health consequences of depression. Our work is hypothesis driven and focused by concentrating on discrete components of the brain stress system that we feel play critical roles in depression. We have added support to our hypothesis of CRH deficiency in atypical depression by demonstrating delayed and diminished plasma ACTH responses to high-intensity exercise and IL-6 administration. We have advanced data in humans suggesting that leptin, produced in fat to inhibit hypothalamic feeding centers, inhibits basal circadian HPA function, raising the possibility that this peripheral signal of nutritional status to the brain may modulate arousal. We have shown that the chronic administration of imipramine to healthy controls down-regulates CRH secretion, and have demonstrated the capacity of non- peptide CRH antagonists that penetrate the blood brain barrier to reduce plasma ACTH secretion in the rat and non-human primate, setting the stage for the use of CRH antagonists in melancholia. We have demonstrated that the pulsatile secretion of plasma ACTH in healthy controls shows the mathematical properties of chaos, rather than of linear periodicity or randomness, setting the stage for testing our hypothesis that a loss of complexity (i.e. of the chaotic pattern) of pulsatile plasma ACTH secretion in the basal state is a diagnostic marker for melancholia. In depressed premenopausal women, bone mineral density is reduced by greater than 15%, a decrement expected to result in a ten year increase in hip fracture of 40%. Determination of the pathogenesis of the decreased bone mineral density in depression will determine the most effective therapeutic intervention (e.g. bisphosphonates vs. growth hormone).